Is PLP2 p.Trp80Arg (c.238T>C) pathogenic?

PLP2 p.Trp80Arg (c.238T>C) is classified Uncertain significance in PLP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: likely pathogenic (0.9825); Ultra-rare (popmax 0.0284%, amr).

How common is PLP2 p.Trp80Arg (c.238T>C) in the general population?

PLP2 p.Trp80Arg (c.238T>C) is ultra-rare (popmax 0.0284%, amr) (gnomAD).

What do computational predictors say about PLP2 p.Trp80Arg (c.238T>C)?

AlphaMissense predicts likely pathogenic (score 0.9825) — an in-silico prediction, not a clinical call.

PLP2 p.Trp80Arg

c.238T>C · rs782640786 · VCV3215365

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0284%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9825	likely pathogenic · top 1% in PLP2
REVEL	0.536	indeterminate
SaProt	LLR -13.56	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 2,690 bp · p 0.75 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0284% Admixed American · 13/45,724 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0132%

Overall 0.00132% 16/1,209,443 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0284%	3,517
Remaining individualsnot grpmax-eligible	0.0042%	23,795
African / African-American	0.00175%	57,073

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PLP2
Protein: p.Trp80Arg
Coding: c.238T>C
MANE Select: NM_002668
dbSNP: rs782640786
Type: single nucleotide variant
Location: chrX:49173270 (GRCh38)
Structure: AlphaFold pLDDT 78.76
Residue 80: the marvel domain

Full PLP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLP2 p.Arg6Cys Benign ★★ same type
PLP2 p.Ala121Pro Uncertain significance ★ ⚠ same type
PLP2 p.Ala2Val Uncertain significance ★ ⚠ same type
PLP2 p.Arg136Trp Uncertain significance ★ ⚠ same type
PLP2 p.Arg21His Uncertain significance ★ ⚠ same type
PLP2 p.Arg87Gln Uncertain significance ★ ⚠ same type
PLP2 p.Gly118Ser Uncertain significance ★ ⚠ same type
PLP2 p.Ile33Val Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/plp2-p-trp80arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown